Tricarbonyl complexes with tridentate chelators for myocardium imaging

ABSTRACT

Chelators of the formulae (I), (II) and (III) 
                         
and tricarbonyl complexes of radioisotopes of Tc and Re bound to them, for use in myocardial imaging.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/515,325, filed May 18, 2009, which claims the priority of PCTApplication PCT/EP2007/010216, filed Nov. 23, 2007, which claims thepriority of GB Application No. 0623482.7, which was filed Nov. 24, 2006.

FIELD OF THE INVENTION

The present invention relates to the field of radiopharmaceuticals fordiagnostic imaging, particularly of the myocardium, and providescationic and lipophilic organometallic complexes of radioisotopes of Tcand Re, and preferably ^(99m)Tc(I) organometallic complexes, whichexhibit marked accumulation in the heart. These complexes contain afac-[^(99m)Tc(CO)₃]⁺ core and are anchored on novel pyrazolyl-containingtridentate chelators having at least one ether group, which are alsowithin the scope of the invention. As these complexes accumulate in themyocardium, they are well suited for cardiovascular imaging.

BACKGROUND OF THE INVENTION

In the field of cardiology, radioactive probes can provide informationon the physiology and pathophysiology of the heart function, e.g. bymyocardial perfusion, metabolism or innervation. Two ^(99m)Tcradiopharmaceuticals, Sestamibi and Tetrafosmin, are commerciallyavailable and approved for myocardial perfusion studies. Theseradiopharmaceuticals, which consist respectively of lipophilic Tc(I) andTc(V) cationic complexes, suffer from low heart/liver and heart/lunguptake ratios, and so are not entirely satisfactory for myocardialperfusion studies. We have therefore been seeking alternative and betterperforming ^(99m)Tc complexes for myocardial imaging, profiting from therecently-introduced so-called organometallic labelling approach. Thisapproach is based on complexes containing the fac-[^(99m)Tc(CO)₃]⁺ coreand is assuming a growing importance in the development of ^(99m)Tcradioactive drugs for diagnostic medical applications.

We have now found that the combination of this organometallic core withappropriate ligands (appropriate in terms of charge, denticity ortopology) provides cationic and lipophilic ^(99m)Tc complexes with thebiological properties required for myocardial imaging.

DETAILED DESCRIPTION OF THE INVENTION

According to one aspect of this invention there are provided tridentatechelators of the type tris(pyrazolyl)methane (R₁C(pz*)₃) andbis(pyrazolyl)amine ((pz*)₂CH(CH₂)_(n)NHR₁ or(pz*)(CH₂)_(n)NR₁(CH₂)_(n)(pz*)) of formulae (I), (II) and (III)respectively:

wherein each of R₁, R₂, R₃ and R₄ is independently hydrogen; a linear orbranched, saturated or unsaturated C₁ to C₉ alkyl; a saturated orunsaturated carbocyclic group; a saturated or unsaturated heterocyclicor heteroaliphatic group with one or more atoms selected from O, N andS, wherein said carbocyclics, heterocyclics and heteroaliphatics areoptionally substituted by one or more linear or branched, saturated orunsaturated C₁ to C₉ alkyls; an ether group —R^(X)—O—R^(Y) or[(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5), wherein R^(X) and R^(Y)are independently linear or branched, saturated or unsaturated C₁ to C₉alkyl, or saturated or unsaturated carbocyclics, any of which alkyland/or carbocyclic groups may be substituted or unsubstituted, with theproviso that at least one of the substituents R₁, R₂, R₃ and R₄ is alinear or macrocyclic ether group of the type —R^(X)—O—R^(Y) or[(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5), respectively, with thefurther proviso that when the tridentate chelator is of the type offormula (1), when R₁ is —R^(X)—O—R^(Y) wherein R^(Y) is substituted, andR₂, R₃, and R₄ are each H, R^(Y) is not substituted apically by afurther tris(pyrazolyl)methane moiety; and when R₁ is —R^(X)—O—R^(Y) andR₂, R₃ and R₄ are each H, R₁ cannot be —CH₂—O—CH₂— (p-^(t)Bu-C₆H₄).

Preferably, the alkyl groups are each independently methyl, ethyl,n-propyl, propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl,n-octyl, or n-nonyl.

More preferably, in each case, the alkyl groups are C₁ to C₃ alkylgroups, i.e. methyl, ethyl, n-propyl, and i-propyl.

If the alkyl and/or aryl groups are substituted, they may be substitutedby one or more groups selected from alkyl, aryl, alkaryl, aralkyl,hydroxy, halogen, amino, nitro, alkoxy or carboxylic acid groups.

Preferably, if neither of R₂ and R₄ is an ether group, they are thesame.

According to another aspect of the invention, R₂ and R₄ are both ethergroups (linear or macrocyclic and preferably the same), in which case R₃is preferably not an ether, but may be any of the other substituentslisted above. In that case R₁ can be any of the substituents listedabove, including an ether group that may be a different ether group fromR₂ and R₄.

According to another aspect of the invention, R₃ is a linear ormacrocyclic ether group. R₂ and R₄ are the same and can be any of thesubstituents listed above, but preferably not ether groups. In that caseR₁ can also be any of the substituents listed above, including an ethergroup that may be the same or different from R₃.

The carbocyclic groups are preferably 5- or 6-membered rings, morepreferably cyclopentyl, cyclohexyl or phenyl groups.

The heterocyclic groups are preferably 5- to 15-membered rings, morepreferably containing oxygen, nitrogen, sulphur, or any combinationthereof, and are most preferably macrocyclic ethers of the type[(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5, provided thatx+y+z=5-15).

The heteroaliphatic groups preferably contain oxygen, nitrogen orsulphur atoms, or any combination thereof, and most preferably are ethergroups of the type —R^(X)—β—R^(Y), wherein R^(X) and R^(Y) are asdefined above.

As can be seen from the above formulae, the linear or macrocyclic ethergroups may be attached to the 3-, 4- and/or 5-positions of the pyrazolylrings. Also, in formula (I) the ether group may be attached to thecentral carbon atom, in formula (II) to the terminal amine, and informula (III) the ether group may be attached to the central nitrogenatom. In one embodiment, at least R₁ is an ether group in the respectiveformulae.

Preferably, the linear ethers are alkyl ethers, but they may also bearyl ethers or alkyl ethers which also contain an aryl substituent.Preferred ethers include those of the general formula (CH₂)_(n)OR,wherein n=1, 2 or 3, and R=methyl, ethyl or n-propyl.

The macrocyclic ethers are preferably crown ethers of the generalformula [(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5).

The ligands shown in formulae (I), (II) and (III) above can stabilizecationic tricarbonyl complexes of the type fac-[M(CO)₃(NNN)]⁺ (Re,^(99m)Tc), wherein NNN represents the tridentate chelator of any of theformulae I-III.

According to another aspect of the invention, there is provided aprocess for the preparation of tridentate chelators of formulae (I),(II) and (III), comprising contacting a compound of the formula

with a compound selected from a trihalomethane, a compound of theformula

or a compound of the formula Hal-(CH₂)_(n)—NR¹—(CH₂)_(n)-Hal (whereinHal=a halogen), and reacting a subsequent product with an alkyl halide,aryl halide, or a halide substituted ether compound, wherein each of R₁,R₂, R₃ and R₄ is independently hydrogen; a linear or branched, saturatedor unsaturated C₁ to C₉ alkyl; a saturated or unsaturated carbocyclicgroup; a group of formula CO₂R₅ or (CH₂)_(n)OH wherein R₅ isindependently hydrogen or a linear or branched, saturated or unsaturatedC₁ to C₉ alkyl and n=1-6; a saturated or unsaturated heterocyclic orheteroaliphatic group with one or more atoms selected from O, N and S,wherein said carbocyclics, heterocyclics and heteroaliphatics areoptionally substituted by one or more linear or branched, saturated orunsaturated C₁ to C₉ alkyls; an ether group —R^(X)—O—R^(Y) or[(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5), wherein R^(X) and R^(Y)are independently linear or branched, saturated or unsaturated C₁ to C₉alkyl, or saturated or unsaturated carbocyclics, any of which alkyland/or carbocyclic groups may be substituted or unsubstituted, with theproviso that at least one of the substituents R₁, R₂, R₃ and R₄ is alinear or macrocyclic ether group of the type —R^(X)—O—R^(Y) or[(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5), respectively, with thefurther proviso that when the tridentate chelator is of the type offormula (I), when R₁ is —R^(X)—O—R^(Y) wherein R^(Y) is substituted, andR₂, R₃, and R₄ are each H, R^(Y) is not substituted apically by afurther tris(pyrazolyl)methane moiety; and when R₁ is —R^(X)—O—R^(Y) andR₂, R₃ and R₄ are each H, R₁ cannot be —CH₂—O—CH₂— (p-^(t)Bu-C₆H₄).

According to another aspect of the invention, tricarbonyl complexes ofradioisotopes of Tc or Re bound to chelators of any of formulae (I),(II), or (III) above are also provided.

The radioisotope is preferably ^(99m)Tc. The ^(99m)Tc complexes canaccumulate in the heart, therefore being useful in radiopharmaceuticalsfor myocardial imaging.

According to a further aspect of the invention there is provided acomposition comprising a tridentate chelator as described above and amixture of sodium boranocarbonate, sodium borate and sodium carbonate.Optionally, a transfer ligand may also be incorporated into thecomposition. Examples of such transfer ligands are salts of a weakorganic acid, i.e. an organic acid having a pKa in the range 3 to 7,with a biocompatible cation. Such weak organic acids include aceticacid, citric acid, tartaric acid, gluconic acid, glucoheptonic acid,benzoic acid, phenols or phosphonic acids. Particularly, the transferligands comprise tartrate, gluconate, citrate, and/or glucoheptonatesalts. Preferably, these compositions are in lyophilised form in asterile vial.

There is also provided a composition comprising a tridentate chelator ofany of formulae (I), (II), or (III) and a filler material. By fillermaterial it is meant any material which can be combined with thecomposition to enable the formation of tablets or pellets of thecomposition. Exemplary filling materials include, but are not limitedto, inositol, lactose and saccharose.

If desired, this composition may also contain an anti-oxidant substance,such as but not limited to gentisic acid, ascorbic acid or methionine.

There is also provided a process for the preparation of a tricarbonylcomplex of radioisotopes of Tc or Re bound to chelators of any offormulae (I), (II), or (III), comprising contacting a compound offormula [M(X)₃(CO)₃]⁺, wherein M=Tc or Re and X═H₂O, MeOH or a halogen,with a tridentate chelator in an alcoholic or aqueous solvent, at a pHof about 6 or less.

Alternatively, the compound of formula [M(X)₃(CO)₃]⁺ can be contactedwith a composition comprising a tridentate chelator of any of formulae(I), (II), or (III) and a mixture of sodium boranocarbonate, sodiumborate and sodium carbonate.

The pH of the reaction is preferably about 4 or less, and the alcoholicsolvent is preferably ethanol.

The compound of formula [M(X)₃(CO)₃]⁺ can be prepared by adding^(99m)Tc-pertechnetate in saline (which is preferably obtained from a⁹⁹Mo/^(99m)Tc generator), or a perrhenate complex, to a compositioncomprising sodium boranocarbonate, sodium borate and sodium carbonate.An example of such a composition is IsoLink®, which comprises sodiumboranocarbonate, sodium borate, sodium carbonate and a tartrate salt.

A general mode of preparation of the tricarbonyl complex ofradioisotopes of Tc or Re bound to chelators of any of formulae (I),(II), or (III), involves a pertechnetate or perrhenate being added to asolution containing the mixture comprising sodium boranocarbonate,sodium borate and sodium carbonate, and this is then heated to yield thetricarbonyl precursor [M(H₂O)₃(CO)₃]⁺ (M=Tc, Re). The solution (whichhas a pH of about 10.5) is acidified to about pH 4, mixed with atridentate chelator ligand and heated again to allow the reactionbetween the tricarbonyl complex and the ligand.

The boranocarbonate-containing composition is used to reduce thepertechnetate (or perrhenate) from oxidation state VII to I and, at thesame time, to generate carbon monoxide which will coordinate andstabilize the Tc(I) in [Tc(H₂O)₃(CO)₃]⁺.

There is also provided a method of myocardial imaging comprisingadministering an imaging composition comprising an effective amount of atricarbonyl complex of radioisotopes of Tc or Re bound to chelators ofany of formulae (I), (II), or (III) to a patient. Preferably, theimaging composition is injected intravenously into the patient, who iseither at rest or has undergone exercise prior to administration, wherean assessment of myocardial bloodflow is necessary. SPECT or planarscintigraphy is then performed after a relevant period post injectionand the results of the biodistribution of the radioactive compound inthe myocardium are evaluated.

The inclusion of at least one ether substituent in the tridentatechelator compounds is important. Lipophilic and cationic ^(99m)Tccomplexes can cross the membranes of cardiac cells by free diffusion,and it is believed that their accumulation in the heart originates fromnegative mitochondrial membrane potentials. The ether substituents tunethe lipophilicity of the complexes to improve both heart uptake andexcretion kinetics, especially clearance from the liver, as the ethergroups can increase the likelihood of the complex being metabolised bythe liver. Such behaviour will improve the target-to-background ratios.

Some synthetic procedures for chelators of formulae (I) to (III) and forthe respective organometallic complexes with rhenium and technetium aregiven in schemes 1 and 2 respectively.

Some detailed but non-limiting examples are given below, showing howsome of the chelators and their respective complexes with thefac-[M(CO)₃]⁺ (where M=^(99m)Tc or Re) moieties may be synthesised, anddemonstrating the affinity of such complexes for the myocardium.

Although ^(99m)Tc is the preferred radionuclide in the invention, itwill be understood by those skilled in the art that other radionuclidesmay be used.

BRIEF DESCRIPTION OF THE FIGURES

In the examples reference is made to the following figures:

FIG. 1: Synthesis of representative examples of chelators of formula Ihaving ether groups at the central carbon atom.

FIG. 2: Synthesis of representative examples of chelators of formula Ibearing ether groups at 4-position of pyrazole.

FIG. 3: Synthesis of a representative example of chelators of formula Ihaving an ether group at the 3- and 5-positions of the pyrazolyl ring.

FIG. 4: ORTEP drawing of the cation of compound 8([{HC[3,5-(CH₃OCH₂)₂pz]₃}₂Na]+).

FIG. 5: Synthesis of a representative example of chelators of formula Ihaving ether groups in the 3-, 4- and 5-positions of the pyrazolyl ring.

FIG. 6: Synthesis of a representative example of chelators of formula IIhaving ether groups at the primary amine.

FIG. 7: Synthesis of a representative example of chelators of formulaIII having ether groups at the secondary amine and/or at the 3- and5-position of the pyrazolyl rings.

FIG. 8: Synthesis of Re complexes with a representative example ofchelators of formula I.

FIG. 9: ¹H NMR spectrum of a rhenium complex with a chelator of formulaI having an ether group at the central carbon atom.

FIG. 10: ¹H NMR spectrum in CDCl₃ of a rhenium complex with a chelatorof formula I having ether groups at the 3- and 5-positions of thepyrazolyl rings.

FIG. 11: Molecular structure of a Re(I) tricarbonyl complex with one ofthe chelators of class I.

FIG. 12: Synthesis of ^(99m)Tc(I) tricarbonyl complexes with chelatorsof formulae I and II.

FIG. 13: HPLC chromatogram of a ^(99m)Tc(I) tricarbonyl complex with achelator of formula I and comparison with its Re congener.

EXAMPLES

Instruments

All chemicals and solvents were of reagent grade and were used withoutpurification unless stated otherwise. ¹H and ¹¹C NMR spectra wererecorded on a Varian Unity 300 MHz spectrometer; ¹H and ¹¹C chemicalshifts (ppm) were referenced with the residual solvent resonancesrelative to tetramethylsilane. IR spectra were recorded on aPerkin-Elmer 577 spectrometer as KBr pellets. C, H and N analyses wereperformed on an EA 110 CE Instruments automatic analyser. Na[^(99m)TcO₄]was eluted from a Mallinckrodt Med. Inc. generator, using 0.9% saline.HPLC analysis of the complexes was performed on a Perkin-Elmer LC pump200 coupled to a LC 290 tunable UV/Vis detector and to a BertholdLB-507A radiometric detector. Separations were achieved on a Nucleosilcolumn (10 μm, 250 mm×4 mm), using a flow rate of 1 mL/min; UVdetection, 254 nm.

Unless otherwise stated, reactions were carried out at normal pressureand under a nitrogen atmosphere. Work-ups were carried out in air.

Example 1 Production of Chelators of Formula I Having an Ether Group atthe Central Carbon Atom

The synthesis of this type of chelators was accomplished viadeprotonation of 2,2,2-tris(pyrazolyl)ethanol followed by its reactionwith adequate alkyl iodides (FIG. 1).

Example 1a O-methyl-1,1,1-tris(pyrazolyl)ethanol: CH₃OCH₂C(pz)₃(compound 1)

To a stirred suspension of NaH (34 mg, 1.42 mmol) in THF (10 mL) wasadded, at room temperature (20-25° C.), 2,2,2-tris(pyrazolyl)ethanol(300 mg, 1.23 mmol) dissolved in the same solvent (10 mL), and themixture was stirred for 1 h. After cooling to 0° C., a solution ofmethyl iodide (873 mg, 6.15 mmol) in THF (5 mL) was added dropwise. Theresulting mixture was warmed to room temperature (20-25° C.) and stirredfor about 16 h. After evaporation of THF under vacuum, the residue wasextracted twice with 10 mL of diethyl ether. Following washing of theether extracts with distilled water, compound 1 was recovered in theform of a colourless oil, after drying the organic phase under vacuum.Yield: 97% (307 mg, 1.19 mmol).

¹H NMR (CDCl₃, δ ppm): 7.64 (3H, d, H-5 (pz)), 7.34 (d, 3H, H-3 (pz)),6.32 (dd, 3H, H-4 (pz)), 5.03 (s, 2H, CH ₂), 3.38 (s, 3H, CH ₃O). ¹³CNMR (CDCl₃, δ ppm): 141.3 (C-3 (pz)), 130.7 (C-5 (pz)), 106.5 (C-4(pz)), 89.5 (C-(pz)₃), 75.5 (CH₂), 59.9 (CH₃O).

Example 1b O-ethyl-1,1,1-tris(pyrazolyl)ethanol: CH₃CH₂OCH₂C(pz)₃(compound 2)

Compound 2 is a colourless oil with tendency to solidify on standing,which was obtained as above described for compound 1, starting from 305mg (1.25 mmol) of 2,2,2-tris(pyrazolyl)ethanol. Yield: 66% (225 mg, 0.83mmol).

¹H NMR (CDCl₃, δ ppm): 7.63 (3H, d, H-5 (pz)), 7.40 (d, 3H, H-3 (pz)),6.31 (dd, 3H, 3H, H-4 (pz)), 5.05 (s, 2H, CH ₂), 3.50 (q, 2H, OCH₂CH₃),1.09 (tr, 3H, OCH₂CH ₃). ¹³C NMR (CDCl₃, δ ppm): 141.2 (C-3 (pz)), 130.9(C-5 (pz)), 106.4 (C-4 (pz)), 89.7 (C-(pz)₃), 73.5 (CH₂), 67.9 (CH₂),15.0 (CH₃).

Example 1c O-n-propyl-1,1,1-tris(pyrazolyl)ethanol: CH₃(CH₂)₂OCH₂C(pz)₃(compound 3)

Compound 3 is a colourless oil which was obtained as above described forcompound 1, starting from 350 mg (1.43 mmol) of2,2,2-tris(pyrazolyl)ethanol. Yield: 52% (212 mg, 0.74 mmol).

¹H NMR (CDCl₃, δ ppm): 7.63 (3H, d, H-5 (pz)), 7.40 (d, 3H, H-3 (pz)),6.31 (dd, 3H, H-4 (pz)), 5.05 (s, 2H, CH ₂), 3.40 (tr, 2H, OCH ₂), 1.47(m, 2H, CH ₂), 0.77 (tr, CH ₃).

Example 2 Production of Chelators of Formula I Having an Ether Group atthe 4-Position of the Pyrazolyl Ring Example 2atris[3,5-Me₂-4-(2-methoxyethyl)pyrazolyl]methane,HC(3,5-Me₂-4-CH₃OCH₂CH₂pz)₃ (compound 4) (FIG. 2)

Ethyl 2-(3,5-dimethyl-1H-pyrazol-4-yl)acetate: To a solution of ethyl3-acetyl-4-oxopentanoate (synthesized as described D. P. Shrout and D.A. Lightner, Synth. Commun. 20 (1990), 2075) (9.676 g, 51.96 mmol) inethanol, at 0° C., was added slowly a solution of hydrazine hydrate(2.990 g, 59.75 g) in absolute ethanol. The reaction mixture was warmedto room temperature and stirred for 2 hours. After removing ethanolunder vacuum, dichloromethane and water were added to the crude productand the organic layer was separated. The aqueous layer was extractedfurther with dichloromethane and the combined organic extracts werewashed with water. After drying over MgSO₄ and evaporation of thesolvent under reduced pressure, the pyrazole was isolated as a yellowoil. Yield: 72% (6.777 g, 37.2 mmol).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 4.09 (2H, q, 7 Hz, CH₂), 3.32 (2H, s,CH₂), 2.21 (6H, s, CH₃), 1.22 (3H, t, 7 Hz, CH₃). ¹³C NMR (75.37 MHz,CDCl₃, δ (ppm)): 171.5 (COOEt), 143.0 (C-pz), 108.6 (C-pz), 60.7 (CH₂),29.4 (CH₂), 14.2 (CH₃), 10.9 (CH₃).

3,5-dimethyl-4-ethylacetate-1-tritylpyrazole: To a solution of3,5-dimethyl-4-ethyl-acetatepyrazole (1.939 g, 10.6 mmol) in dry THF wasadded sodium hydride (556 mg, 60% in mineral oil, 13.8 mmol) and themixture was stirred at room temperature for 1 hour. Triphenylmethylchloride (2.955 g, 10.6 mmol) was then added, and the reaction run for 3days at room temperature. After this time, the solvent was evaporatedand the solid was stirred in water, filtered and washed with water anddiethyl ether. After drying under vacuum the pyrazole was obtained as asolid. Yield: 46% (2.047 g, 4.82 mmol).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 7.30-7.00 (15H, m, Ph), 4.09 (2H, q,7.2 Hz, CH₂), 3.29 (2H, s, CH₂), 2.15 (3H, s, CH₃), 1.42 (3H, s, CH₃),1.20 (3H, t, 7 Hz, CH₃). ¹³C NMR (75.37 MHz, CDCl₃, δ (ppm)): 171.5(COOEt), 144.7 (C-pz), 141.1 (Ph), 139.6 (C-pz), 130.3, 127.3, 127.1(Ph), 111.6 (C-pz), 60.6 (CH₂), 30.0 (CH₂), 14.2 (CH₃), 13.0 (CH₃), 12.4(CH₃).

3,5-dimethyl-4-hydroxyethyl-1-tritylpyrazole: To a solution of3,5-dimethyl-4-ethylacetate-1-tritylpyrazole (2.442 g, 5.75 mmol) in dryTHF, at 0° C., LiAlH₄ in ether (1M, 11.5 mmol) was added dropwise. Afterstirring at room temperature for about 16 h, the reaction was quenchedby addition of water (1.4 ml) and NaOH (10%, 0.5 ml). The suspension wasfiltered off and the supernatant was extracted with dichloromethane. Theorganic phase was dried over MgSO₄ and vacuum dried, yielding the titlecompound as a yellow solid. Yield: 90% (1.980 g, 5.176 mmol).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 7.30-7.00 (15H, m, Ph), 3.60 (2H, t,6.8 Hz, CH₂), 2.57 (2H, t, 6.8 Hz, CH₂), 2.15 (3H, s, CH₃), 1.41 (3H, s,CH₃).

3,5-dimethyl-4-ethyl methyl ether-1-tritylpyrazole: To a solution of3,5-dimethyl-4-hydroxyethyl-1-tritylpyrazole (1.910 g, 4.99 mmol) in dryTHF was added a portion of NaH (260 mg, 60% in mineral oil, 6.49 mmol),and the mixture was stirred at room temperature for about 16 h. Methyliodide (1.56 mL, 24.95 mmol) was then added and the reaction stirred for24 h at 20-25° C. After removal of THF under vacuum, the resultingresidue was extracted with dichloromethane, followed by washing withwater. Evaporation of dichloromethane under vacuum yielded the titlecompound as a yellow solid. Yield: 93% (1.834 g, 4.63 mmol).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 7.30-7.00 (15H, m, Ph), 3.32 (2H+3H,CH₂+OCH₃), 2.56 (2H, t, 7.8 Hz, CH₂), 2.15 (3H, s, CH₃), 1.40 (3H, s,CH₃).

3,5-dimethyl-4-ethyl methyl etherpyrazole: A solution of3,5-dimethyl-4-ethyl methyl ether-1-tritylpyrazole (1.832 g, 4.62 mmol)in dichloromethane/methanol (1:2, 72 mL) was treated with CF₃COOH (18ml) and heated at 75° C. for about 16 h. After this time, the mixturewas cooled to room temperature and the solvents were evaporated. Thecrude product was purified by silica-gel chromatography using gradientelution, from 10% n-hexane/90% ethyl acetate to 20% methanol/80% ethylacetate. After evaporation of the solvent from the collected fractions,the isolated pyrazole contained solvated CF₃COOH. To remove the acid,the compound was redissolved in ethyl acetate and washed successivelywith a saturated solution of NaHCO₃ and with water. After drying theorganic phase over MgSO₄ and evaporation of the solvent under vacuum,the title compound was isolated as a slightly yellow oil. Yield: 43%(305 mg, 1.98 mmol).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 3.36 (2H, t, 7.2 Hz, CH₂), 3.32 (3H,s, OCH₃), 2.60 (2H, t, 7.2 Hz, CH₂), 2.19 (6H, s, CH₃). ¹³C NMR (75.37MHz, CDCl₃, δ (ppm)): 142.5 (C-pz), 111.7 (C-pz), 72.8 (CH₂), 58.56(OCH₃), 23.7 (CH₂), 10.8 (CH₃).

HC(3,5-Me₂-4-CH₃OCH₂CH₂pz)₃ (compound 4): Under vigorous stirring,Na₂CO₃ (1.259 g, 1.88 mmol) was slowly added to a mixture of3,5-dimethyl-4-ethyl methyl etherpyrazole (300 mg, 1.9 mmol) andtetrabutyl ammonium bromide (31.3 mg, 0.097 mmol) in H₂O (2.6 ml),occurring a slightly exothermic reaction. After cooling to roomtemperature (20-25° C.), 1.3 mL of chloroform was added and theresulting mixture was heated at reflux for 3 days. After this time, thesolids formed were filtered off and 25 mL of CHCl₃ were added to thesupernatant and the organic phase separated. The organic phase waswashed with water, dried over MgSO₄ and the solvent was removed undervacuum. The residue obtained was purified by silica-gel chromatography(2% methanol/98% CHCl₃) to give the tris(pyrazolyl)methane as a slightlyyellow oil which crystallised at room temperature. Yield: 31% (0.195mmol, 92 mg).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 8.02 (1H, s, CH), 3.32 (6H, t, 7.5 Hz,CH₂), 3.30 (9H, s, OCH₃), 2.57 (6H, t, 7.5 Hz, CH₂), 2.13 (9H, s, CH₃),1.89 (9H, s, CH₃). ¹³C NMR (75.37 MHz, CDCl₃, δ (ppm)): 147.8 (C-pz),138.1 (C-pz), 114.7 (C-pz), 81.2 (CH), 72.6 (CH₂), 58.6 (OCH₃), 24.1(CH₂), 12.3 (CH₃), 9.2 (CH₃).

Example 2b Tris(4-methoxymethylpyrazolyl)methane: HC(4-CH₃OCH₂pz)₃(compound 5)

Ethyl 1-tritylpyrazole-4-carboxylate: Ethyl pyrazole-4-carboxylate (W.Holtzer, G. Seiringer, J. Heterocyclic Chem., 1993, 30, 865) (1.7 g,12.1 mmol) and NaH (680 mg, 60% in mineral oil, 16.94 mmol) reacted indry DMF for 1 h. Then, trityl chloride (3.373 g, 12.1 mmol) was added,and the reaction mixture stirred for 3 days at room temperature. Thetitle compound was recovered as described in example 2a for3,5-dimethyl-4-ethylacetate-1-tritylpyrazole. Yield: 82% (3.79 g, 4mmol).

¹H NMR (CDCl₃, δ ppm): 8.02 (1H, s, H-3 (pz)), 7.91 (1H, s, H-5 (pz)),7.40-7.27 (9H, m, Ph), 7.20-7.00 (6H, m, Ph), 4.25 (2H, q, 7.2 Hz, CH₂), 1.29 (3H, t, 7.2 Hz, CH ₃). ¹³C NMR (CDCl₃, δ ppm): 163.2 (CO),142.3 (3/5-C(pz)), 141.1 (C-Ph)), 135.6 (C-Ph), 130.0 (C-Ph), 127.9(C-Ph), 113.8 (4-C(pz)), 79.4 (N—CPh3), 60.2 (CH₂), 14.4 (CH₃).

1-trityl-4-hydroxymethylpyrazole: The title compound was obtained byreduction of ethyl 1-tritylpyrazole-4-carboxylate (3.785 g, 9.9 mmol)with LiAlH₄ (19.8 mmol) in dry THF (50 mL), as described in example 2afor the synthesis of 3,5-dimethyl-4-hydroxyethyl-1-tritylpyrazole.Yield: 91% (3.06 g, mmol).

¹H NMR (CDCl₃, δ ppm): 7.65 (1H, s, H-3 (pz)), 7.37 (1H, s, H-5 (pz)),7.24-7.30 (9H, m, Ph), 7.08-7.16 (6H, m, Ph), 4.54 (2H, s, CH ₂). ¹³CNMR (CDCl₃, δ ppm): 143.1 (3/5-C(pz)), 139.1 (C-Ph), 131.3 (C-Ph), 130.1(C-Ph), 127.7 (C-Ph), 120.0 (4-C(pz)), 56.2 (CH₂).

1-trityl-4-methoxymethylpyrazole: This compound is obtained by reacting1-trityl-4-hydroxymethylpyrazole (555 mg; 1.63 mmol) in drytetrahydrofuran with sodium hydride (98 mg; 2.44 mmol) and iodomethane(0.5 mL; 8.15 mmol). Yield: 93% (536 mg, 1.51 mmol).

¹H NMR (CDCl₃, δ ppm): 7.63 (1H, s; 3-H(pz)), 7.36 (1H, s, 5-H(pz)),7.25-7.30 (9H, m, Ph), 7.08-7.15 (6H, m, Ph), 4.29 (2H, s, CH₂), 3.31(3H, s, CH₃).

4-methoxymethylpyrazole: CF₃COOH was added to a solution of1-trityl-4-methoxymethylpyrazole in CH₂Cl₂/MeOH (1:1). The mixture washeated at 75-80° C. overnight. After cooling to room temperature, thesolvent was removed under the vacuum and the residue was applied on thetop of a silica-gel column and eluted with methanol/ethyl acetate(5:95). The solvent from the collected fractions was removed undervacuum, and the residue redissolved in ethyl acetate. The title compoundwas recovered as a slightly yellow oil, after washing the organic phasewith a saturated solution of NaHCO₃ and distilled water, followed byremoval of the solvent and prolonged drying under vacuum. Yield: 38% (60mg, 0.54 mmol).

¹H NMR (CDCl₃, δ ppm): 7.57 (2H, s, H-3/5 (pz)), 4.38 (2H, s, CH ₂),3.34 (3H, s, CH ₃).

HC(4-CH₃OCH₂pz)₃ (compound 5): This compound has been synthesized asdescribed in Example 2a for compound 4, starting from4-methoxymethylpyrazole (60 mg, 0.54 mmol). After purification bygradient HPLC (100% aqueous 0.1% CF₃COOH solution→100%.CH₃CN), using aNucleosil column (10 μm, 250 mm×4 mm), compound 5 was recovered as aslightly yellow oil. Yield: 16% (10 mg, 0.029 mmol).

¹H NMR (CDCl₃, δ ppm): 8.24 (1H, s, CH), 7.62 (3H, s, H-3/5 (pz)), 7.54(3H, s, H-3/5 (pz)), 4.31 (6H, s, 6.9 Hz, CH ₂) 3.32 (9H, s, OCH ₃). ¹³CNMR (CDCl₃, δ ppm): 141.7 (C-3/5(pz)), 128.7 (C-3/5(pz)), 120.1((C-4(pz)), 83.3 (CH), 65.1 (CH₂), 57.9 (OCH₃). FTICR-MS(+) (m/z):346.2[M]⁺ (12).

Tris(4-ethoxymethylpyrazolyl)methane: HC(4-CH₃CH₂OCH₂pz)₃ (compound 6)

1-trityl-4-ethoxymethylpyrazole: This compound is a slightly yellowsolid and has been obtained as described in 2b for1-trityl-4-methoxymethylpyrazole, starting from1-trityl-4-hydroxymethylpyrazole (1.250 g; 3.67 mmol), sodium hydride(221 mg; 5.51 mmol) and iodoethane (1.5 mL; 18.35 mmol), as described inexample 2a for 3,5-dimethyl-4-methoxyethyl-1-tritylpyrazole. Yield: 87%(1.174 g, 3.19 mmol).

¹H NMR (CDCl₃, δ ppm): 7.64 (1H, s, 3-H(pz)), 7.35 (1H, s, 5-H(pz)),7.26-7.29 (9H, m, Ph), 7.10-7.13 (4H, m, Ph), 4.33 (2H, s, CH₂), (2H, q,7.2 Hz, CH₂), 1.18 (3H, t, 7.2 Hz, CH₃). ¹³C(CDCl₃, δ ppm): 143.2(3/5-C(pz)), 139.9 (C-Ph)), 131.8 (C-Ph), 130.1 (C-Ph), 127.7 (C-Ph),117.1 (4-C(pz)), 65.4 (CH₂)., 63.5 (CH₂), 15.2 (CH₃).

4-ethoxymethylpyrazole: 1-trityl-4-ethoxymethylpyrazole (1.800 g, 4.88mmol) was dissolved in a mixture of ethanol/acetone (15 ml/5 ml) and 30mL of 2N HCl was added to the resulting solution. The mixture was heatedat 80° C. for 2 h. After cooling to room temperature, the reactionmixture was filtered and washed with dichloromethane. The aqueous layerwas basified with 2N NaOH and extracted with dichloromethane. Theorganic layers were combined, dried over MgSO₄ and the solvent wasevaporated under vacuum yielding compound 4-ethoxymethylpyrazole as awhite oil. Yield: 44% (270 mg, 2.14 mmol).

¹H NMR (CDCl₃, δ ppm): 7.57 (2H, s, H-3/5 (pz)), 4.43 (2H, s, CH₂), 3.50(2H, q, 6.9 Hz, CH ₂), 1.20 (3H, t, 6.9 Hz, CH3). ¹³C NMR (CDCl₃, δppm): 133.6 (C-3/5 (pz)), 117.9 (C-4 (pz)), 65.3 (CH₂), 63.3 (CH₂), 15.1(CH₃).

HC(4-CH₃CH₂OCH₂pz)₃ (compound 6): This compound has been obtained asdescribed in Example 2a for compound 4. Starting with4-ethoxymethylpyrazole (234 mg, 1.86 mmol), and after convenientwork-up, a white microcrystalline solid was obtained. Yield: 73% (176mg, 0.453 mmol).

¹H NMR (CDCl₃, δ ppm): 8.25 (1H, s, CH), 7.60 (3H, s, H-3/5 (pz)), 7.55(3H, s, H-3/5 (pz)), 4.32 (6H, s, 6.9 Hz, CH ₂) 3.45 (6H, q, OCH ₂),1.15 (9H, t, CH ₃). ¹³C NMR (CDCl₃, δ ppm): 141.6 (C-3/5(pz)), 128.6(C-3/5(pz)), 120.2 ((C-4(pz)), 83.15 (CH), 65.6 (CH₂), 63.0 (CH₂), 15.0(CH₃). FTICR/MS(+) (m/z): 388.2 [M]⁺ (50%).

Example 3 Production of Chelators of Formula I Having Alkoxy Groups at3-,5-Positions of the Pyrazolyl Ring Example 3atris[3,5-(methoxymethyl)pyrazolyl]methane, HC [3,5-(CH₃OCH₂)₂pz]₃(compound 7) (FIG. 3).

Dimethyl 1-trityl-3,5-pyrazoledicarboxylate: This compound is a whitemicrocrystalline solid that has been isolated following the methodologydescribed in 2b for ethyl-1-tritylpyrazole-4-carboxylate, by reaction ofwith dimethyl-3,5-pyrazoledicarboxylate (1.411 g, 7.66 mmol) with sodiumhydride (250 mg, 10.41 mmol) in dry dimethylformamide (20 mL), followedby treatment with trityl chloride (2.135 g, 7.66 mmol). Yield: 98%(3.200 g, 7.50 mmol).

¹H NMR (CDCl₃, δ ppm): 7.34 (1H, s, H-4 (pz)), 7.26 (9H, m, Ph), 7.08(6H, m, Ph), 3.83 (3H, s, CH ₃), 3.26 (3H, s, CH ₃).

1-trityl-3,5-bis(hydroxymethyl)pyrazole: To a solution of dimethyl1-trityl-3,5-pyrazoledicarboxylate (3.200 g, 7.50 mmol) in dry THF (50mL) were added 30 mL of 1.0 M LiAlH₄ in Et₂O. The resulting solution wasstirred for about 16 h at room temperature (20-25° C.). After this time,the reaction was quenched by the slow addition of 1 mL of distilledwater, followed by addition of 1 mL of 10% NaOH and 2.4 mL of water. Thesolids formed were removed by filtration, and 50 mL of dichloromethanewas added to the filtrate. The organic phase was separated, washed withdistilled water and a white microcrystalline solid was obtained afterevaporation of the solvent under vacuum. Yield: 90% (2.843 g, 6.71mmol).

¹H NMR (CDCl₃, δ ppm): 7.28 (9H, m, Ph), 7.08 (6H, m, Ph), 6.44 (1H, s,H-4 (pz)), 4.62 (2H, d, CH ₂), 3.83 (2H, d, CH ₂), 2.10 (1H, tr, OH),0.70 (1H, tr, OH).

1-trityl-3,5-bis(methoxymethyl)pyrazole: This compound is a whitemicrocrystalline solid that has been obtained by reacting1-trityl-3,5-bis(hydroxymethyl)-pyrazole (2.483 g, 6.71 mmol) withsodium hydride (670 mg; 16.8 mmol) and methyl iodide (4.2 mL; 67.5mmol), as described above in examples 2a and 2b for congener pyrazolederivatives. Yield: 98% (2.606 g, 6.55 mmol).

¹H NMR (CDCl₃, δ ppm): 7.26 (9H, m, Ph), 7.09 (6H, m, Ph), 6.45 (1H, s,H-4 (pz)), 4.39 (2H, s, CH ₂), 3.48 (2H, s, CH ₂), 3.34 (3H, s, CH ₃),2.97 (3H, s, CH ₃).

3,5-bis(methoxymethyl)pyrazole: This compound was obtained bydeprotection of trityl-3,5-bis(hydroxymethyl)pyrazole (2.606 g, 6.54mmol), as described in example 2b for 4-methoxymethylpyrazole. Yield:58% (589 mg, 3.80 mmol).

¹H NMR (CDCl₃, δ ppm): 10.72 (1H, br, NH), 6.19 (1H, s, H-4 (pz)), 4.45(4H, s, CH ₂), 3.32 (6H, s, CH ₃). ¹³C NMR (CDCl₃, δ ppm): 145.2 (C-3/5(pz)), 103.4 (C-4 (pz)), 66.5 (CH ₂), 58.0 (CH ₃).

tris[3,5-(methoxymethyl)pyrazolyl]methane, HC[3,5-(CH₃OCH₂)₂pz]₃(compound 7): To a solution of 3,5-bis(methoxymethyl)pyrazole (331 mg,2.14 mmol) and [NBu₄]Br (35 mg, 0.11 mmol) in distilled water (3 mL) wasslowly added Na₂CO₃ (1.77 g, 2.64 mmol). Then, 1.5 mL of CHCl₃ was addedand the mixture was heated gently under reflux for 3 days. The organicphase was separated, washed with water and dried over MgSO₄. Compound 7was purified by silica-gel flash chromatography usingmethanol/dichloromethane (2:98) as eluent. Yield: 34% (116 mg, 0.24mmol).

Anal. Calcd. for C₂₂H₃₄N₆O₆: C, 55.22; H, 7.16; N, 17.56%. Found: C,55.89; H, 5.49; N, 17.53%.

¹H NMR (CDCl₃, δ ppm): 8.71 (1H, s, CH), 6.33 (3H, s, H-4 (pz)), 4.38(6H, s, CH ₂), 4.30 (6H, s, CH ₂) 3.31 (9H, s, CH ₃) 3.18 (9H, s, CH ₃).¹³C NMR (CDCl₃, δ ppm): 149.7 (C-3/5(pz)), 141.1 (C-3/5(pz)), 107.4(C-4(pz)), 78.7 (C—H), 68.2 (CH₂), 64.6 (CH₂), 57.9, 57.8 (OCH₃).FTICR/MS(+) (m/z): 479.3 [M+H]⁺ (22%).

Example 3b Sodium salt of tris[3,5-(methoxymethyl)pyrazolyl]methane:[{HC[3,5-(CH₃OCH₂)₂pz]₃}₂Na]I (compound 8)

Sodium salt of tris[3,5-(methoxymethyl)pyrazolyl]methane,[{HC[3,5-(CH₃OCH₂)₂pz]₃}₂Na]I (compound 8)

To a solution of Nat (14 mg, 0.093 mmol) in dry THF (2 mL) was addeddropwise a solution of tris[3,5-(methoxymethyl)pyrazolyl]methane(compound 7) (89 mg, 0.186 mmol) in THF. After one hour of reaction atroom temperature, the formed white precipitate was separated and vacuumdried. Yield: 68% (70 mg, 0.063 mmol). Elemental analysis: Found(Calcd.) for C₄₄H₆₈IN₁₂NaO₁₂: C, 48.35 (47.74); H, 5.97 (6.19); N, 15.34(15.18);

¹H NMR (D₂O, δ ppm): 8.55 (1H, s, CH), 6.42 (3H, s, H-4 (pz)), 4.30-4.29(12H, s, CH ₂), 3.20 (9H, s, CH ₃) 3.02 (9H, s, CH ₃); ¹³C NMR (D₂O, δppm): 152.3 (C-3/5(pz)), 143.4 (C-3/5(pz)), 111.3 (C-4(pz)), 79.3 (C—H),69.1 (CH₂), 65.7 (CH₂), 59.7 (OCH₃)., 59.6 (OCH₃). Monocrystals suitablefor X-ray structural analysis were obtained by recrystallization ofcompound 8 from a mixture of acetone/n-hexane.

Example 3c tris[3,5-bis(ethoxymethyl)pyrazolyl]methane,HC[3,5-(CH₃CH₂OCH₂)₂pz]₃ (compound 9)

3,5-bis(ethoxymethyl)pyrazole: This compound has been obtained using thesame methodologies described in Example 3a for3,5-bis(methoxymethyl)pyrazole. Yield: 55% (529 mg, 2.87 mmol).

¹H NMR (CDCl₃, δ ppm): 8.39 (1H, br, NH), 6.20 (1H, s, H-4 (pz)), 4.49(4H, s, CH₂), 3.50 (4H, q, 6.9 Hz, CH₂), 1.17 (6H, t, 6.9 Hz, CH₃). ¹³CNMR (CDCl₃, δ ppm): 145.5 (C-3/5 (pz)), 103.7 (C-4 (pz)), 65.7 (CH₂),64.8 (CH₂), 15.0 (CH₃).

tris[3,5-bis(ethoxymethyl)pyrazolyl]methane, HC [3,5-(CH₃CH₂OCH₂)₂pz]₃(compound 9): Compound 9 has been prepared using the same methodologydescribed for compound 7. Starting from 3,5-bis(ethoxymethyl)pyrazolyl(485 mg, 2.63 mmol) a slightly yellow oil was obtained, after theappropriate work-up. Yield: 47% (230 mg, 0.41 mmol).

¹H NMR (CDCl₃, δ ppm): 8.68 (1H, s, CH), 6.32 (3H, s, H-4 (pz)), 4.41(6H, s, CH ₂), 4.32 (6H, s, CH ₂) 3.46 (6H, q, 6.9 Hz, CH ₂) 3.34 (6H,q, 6.9 Hz, CH ₂), 1.16 (9H, t, 6.9 Hz, CH₃), 1.06 (9H, t, 6.9 Hz, CH₃).¹³C NMR (CDCl₃, δ ppm): 150.0 (C-3/5(pz)), 141.7 (C-3/5(pz)), 107.2(C-4(pz)), 79.0 (C—H), 66.4 (CH₂), 65.8 (CH₂), 65.5 (CH₂), 62.9 (CH₂),15.1, (CH₃), 14.9 (CH₃). FTICR/MS(+) (m/z): 563.4 [M+H]⁺ (46%).

Example 4 Production of a chelator of formula I having alkoxy groups atthe 3-, 4- and 5-positions of the pyrazolyl ring:tris[3,4,5-tris(methoxymethyl)pyrazolyl]methane, HC[3,4,5-(CH₃OCH₂)₃pz]₃(compound 10) (FIG. 5).

Trimethyl-3,4,5-pyrazoletricarboxylate: 3,4,5-Pyrazoletricarboxylic acid(D. Chambers, W. A. Denny, J. Org. Chem., 1985, 50, 4736-4738) (2.15 g,10.7 mmol) was dissolved in methanol (80 mL) and concentrated H₂SO₄(0.85 mL) was added. After overnight reflux, the solvent was evaporatedin the rotary evaporator. The residue was dissolved in water (80 mL) andthe product extracted with CHCl₃ (4×80 mL). The organic phase was driedover MgSO4, separated and the solvent evaporated under vacuum. The crudeproduct was purified by silica-gel chromatography using gradientelution, from 100% CHCl₃ to 100% MeOH. The collected fractions wereevaporated under vacuum and the white solid analysed. Yield: 32% (830mg, mmol).

¹H NMR (CDCl₃, δ ppm): 3.95 (3H, s, COOCH ₃), 3.93 (6H, s, COOCH ₃).

Trimethyl 1-trityl-3,4,5-pyrazoletricarboxylate: The synthesis of thiscompound was done by tritylation oftrimethyl-3,4,5-pyrazoletricarboxylate (1680 mg, 6.94 mmol) using aprocedure similar to the one described in examples 2 and 3 for thesynthesis of other tritylated pyrazole derivatives. The startingpyrazole reacted with sodium hydride (405 mg, 10.13 mmol) in drydimethylformamide (80 mL) for 30 min at room temperature. Then, tritylchloride (1935 mg, 6.94 mmol) was added and the reaction mixture stirredovernight at room temperature. After removal of the solvent undervacuum, the resulting residue was washed with distilled water, n-hexane,and finally dried under vacuum to afford the title compound, as a whitemicrocrystalline solid. Yield: 90% (3.034 g, 6.26 mmol).

¹H NMR (CDCl₃, δ ppm): 7.30-7.24 (9H, m, Ph), 7.13-7.09 (6H, m, Ph),3.84 (3H, s, COOCH ₃), 3.80 (3H, s, COOCH ₃), 3.19 (3H, s, COOCH ₃).

1-trityl-3,4,5-tris(hydroxymethyl)pyrazole: To a solution of trimethyl1-trityl-3,4,5-pyrazoletricarboxylate (3.034 g, 6.26 mmol) in dry THF(60 mL) were added 50 mL of 1.0 M LiAlH₄ in Et₂O. The resulting solutionwas stirred for about 16 h at room temperature (20-25° C.). After thistime, the reaction was quenched by the slow addition of 1.5 mL ofdistilled water, followed by addition of 1.5 mL of 10% NaOH and 3.5 mLof water. The solids formed were removed by filtration, and 80 mL ofdichloromethane was added to the filtrate. The organic phase wasseparated, washed with distilled water (70 mL) and, after separationfrom the aqueous phase, was dried over MgSO4. After separation of theorganic phase, the solvent was evaporated under vacuum yielding ayellowish solid. Yield: 73% (1.823 g, 4.54 mmol).

¹H NMR (CDCl₃, δ ppm): 7.29 (9H, m, Ph), 7.08 (6H, m, Ph), 4.67 (2H, d,CH ₂), 4.63 (2H, d, CH ₂), 4.05 (2H, d, CH ₂), 2.68 (1H, tr, OH), 2.41(1H, tr, OH), 0.84 (1H, tr, OH).

1-trityl-3,4,5-tris(methoxymethyl)pyrazole: To a solution of1-trityl-3,4,5-tris(hydroxymethyl)-pyrazole (1.823 g, 4.54 mmol) in dryTHF (60 mL) was added 685 mg of a 60% NaH suspension (28.5 mmol), andthe mixture was stirred for 4 h at room temperature (20-25° C.). Afterthis time, 4.35 mL of methyl iodide (mmol) was added and the mixture wasallowed to react for 2 h. The solvent was removed under vacuum and theresidue redissolved in dichloromethane (100 mL) and the organic phasewas washed with distilled water. The organic phase was separated, driedover MgSO4 and the filtrate was vacuum dried. The white microcrystallinesolid was formulated as the above mentioned compound based on NMRanalysis. Yield: 98% (2.12 g, mmol).

¹H NMR (CDCl₃, δ ppm): 7.26 (9H, m, Ph), 7.12 (6H, m, Ph), 4.44 (4H, d,CH ₂), 3.78 (2H, s, CH ₂), 3.32 (3H, s, CH ₃), 3.31 (3H, s, CH ₃), 2.77(3H, s, CH ₃).

3,4,5-tris(methoxymethyl)pyrazole: This compound is a whitemicrocrystalline solid obtained by deprotection of1-trityl-3,4,5-tris(methoxymethyl)pyrazole (2.125 g, 4.80 mmol), asdescribed in example 2b for 4-methoxymethylpyrazole. Yield: 78% (752 mg,3.75 mmol).

¹H NMR (CDCl₃, δ ppm): 10.85 (1H, br, NH), 4.51 (4H, s, CH₂), 4.37 (2H,s, CH ₂), 3.35 (6H, s, CH ₃) 3.29 (3H, s, CH ₃). ¹³C NMR (CDCl₃, δ ppm):144.1 (C-3/5 (pz)), 113.7 (C-4 (pz)), 65.5 (CH₂), 63.7 (CH₂), 58.1(CH₃), 57.7 (CH₃).

tris[3,4,5-(methoxymethyl)pyrazolyl]methane, HC [3,4,5-(CH₃OCH₂)₃pz]₃(compound 10). To a solution of 3,4,5-tris(methoxymethyl)pyrazole (202mg, 1.01 mmol) and [NBu₄]Br (16.8 mg, 1.01 mmol) in distilled water (1.5mL) was slowly added Na₂CO₃ (660 mg, mmol). Then, 0.8 mL of CHCl₃ wasadded and the mixture was heated gently under reflux for 5 days. Theorganic phase was separated, washed with water and dried over MgSO₄.Compound was purified by silica-gel flash chromatography usingmethanol/dichloromethane (2:98) as eluent. Yield: 34% (116 mg, 0.24mmol).

¹H NMR (CDCl₃, δ ppm): 8.83 (1H, s, CH), 4.42 (6H, s, CH ₂), 4.38 (6H,s, CH ₂), 4.37 (6H, s, CH ₂) 3.25 (18H, s, CH ₃) 3.13 (9H, s, CH ₃).).¹³C NMR (CDCl₃, δ ppm): 148.5 (C-3/5 (pz)), 139.6 (C-3/5 (pz)), 117.9(C-4 (pz)), 78.7 (CH), 67.1 (CH₂), 63.6 (CH₂), 57.8 (CH₃), 57.5 (CH₃).

Example 5 Production of a Chelator of Class II Having an Alkoxy Group atthe Primary Amine Example 5aN-(2-methoxyethyl)-2,2-di(1H-pyrazol-1-yl)ethanamine:MeO(CH₂)₂NHCH₂CH(pz)₂ (compound 11) (FIG. 6)

To a solution of 2,2′-bis(pyrazolyl)ethanamine (327 mg, 1.8 mmol) in dryethanol (15 mL) was added excess of 1-chloro-2-methoxyethane (526 μL;5.8 mmol), K₂CO₃ (1.281 g, 9.2 mmol) and KI (30 mg, 0.18 mmol), and themixture refluxed for 4 days. After this time, the solvent was removedunder vacuum and the residue was applied on a silica gel column whichwas eluted with MeOH/CHCl₃ (5:95). Removal of the solvent from thecollected fractions yielded the title compound in the form of a brownoil. Yield: 21% (89 mg, 0.38 mmol).

¹H NMR (CDCl₃): δ_(H) 7.58 (d, H-3/5 (pz), 2H), 7.53 (d, H-3/5 (pz),2H), 6.51 (t, CH, 1H), 6.25 (t, H-4 (pz), 2H), 3.69 (d, —NHCH ₂CH, 2H),3.41 (t, OCH ₂, 2H), 3.28 (s, —OCH, 3H), 2.27 (t, NCH ₂CH₂, 2H). ¹³C NMR(CDCl₃): δ_(C) 140.3 (C-3 (pz)), 128.9 (C-5 (pz)), 106.6 (C-4 (pz)),75.0 (CH), 71.8 (CH₂), 58.8 (CH₃O), 51.6 (CH₂), 48.7 (CH₂). FT/ICR-MS(+) (m/z): 236.2 [M+H]⁺ (10%).

Example 6 Production of a Chelator of Class III Having Ether Groups atthe Secondary Amine and/or at the 3- and 5-Position of the PyrazolylRings Example 6abis(2-(3,5-bis(methoxymethyl)-1H-pyrazol-1-yl)ethyl)amine:{3,5-(CH₃OCH₂)₂}pz(CH₂)₂NH(CH₂)_(2{)3,5-(CH₂OCH₃)₂ pz)} (compound 12)(FIG. 7)

A suspension of NaH (0.240 g, 10 mmol) in dry DMF (20 mL) was slowlyadded to 3,5-bis(methoxymethyl)pyrazole (500 mg; 3.42 mmol) in dry DMF(10 mL). The reaction mixture was left at room temperature for 4 h. Asolution of bis-(2-chloroethyl)amine hydrochloride (305 mg, 1.71 mmol)was then slowly added, and the mixture reacted at room temperature for 5days. The solvent was evaporated and the crude compound was purified bysilica gel chromatography (eluent: CHCl₃/MeOH (95:5)). The collectedfractions were vacuum dried affording compound 12 as slightly yellow oilYield: 40% (26.1 mg; 0.68 mmol).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 6.18 (s, H-4 (pz), 2H), 4.39 (d, —CH₂,8H), 4.14 (t, —CH₂, 4H), 3.35 (s, —OCH₃, 6H), 3.28 (s, —OCH₃, 6H), 3.00(t, —CH₂, 4H); ¹³C NMR (75.37 MHz, CDCl₃, δ (ppm)) 148.3, 139.4, 106.1,68., 64.3, 57.9, 57.6, 49.0, 48.9.

Example 6b2-(3,5-bis(methoxymethyl)-1H-pyrazol-1-yl)-N-(2-(3,5-bis(methoxymethyl)-1H-pyrazol-1-yl)ethyl)-N-(2-methoxyethyl)ethanamine:{3,5-(CH₃OCH₂)₂}pz(CH₂)₂N((CH₂)₂OMe)(CH₂)_(2{)3,5-(CH₂OCH₃)₂pz)}(compound 13) (FIG. 7)

Ethyl2-(bis(2-(3,5-bis(methoxymethyl)-1H-pyrazol-1-yl)ethyl)amino)acetate. Toa solution of compound 12 (0.261 g, 0.68 mmol) in acetonitrile (15 mL)was added potassium carbonate (193 mg, 1.4 mmol) and potassium iodide (6mg, 0.03.4 m mol). To this suspension was then added ethyl bromo acetate(155 μL, 1.4 mmol). The reaction mixture was refluxed overnight, undernitrogen. The supernatant was separated and the solvent evaporated undervacuum. The orange solid obtained was analysed. Yield: (280 mg; 0.6mmol).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 6.15 (s, H-4 (pz), 2H), 4.39 (d, —CH₂,8H), 4.13-4.06 (q, —CH₂, 8H), 4.01 (t, —CH₂, 4H), 3.37-3.28 (m,—OCH₃+—CH₂, 12+2H), 3.07 (t, —CH₂, 4H), 1.21 (t, —CH₃, 3H).

2-(bis(2-(3,5-bis(methoxymethyl)-1H-pyrazol-1-yl)ethyl)amino)ethanol:This compound has been obtained by reacting a solution of ethyl2-(bis(2-(3,5-bis(methoxymethyl)-1H-pyrazol-1-yl)ethyl)amino)acetate(280 mg; 0.6 mmol) in dry THF (10 mL) with LiAlH₄. The title compoundwas isolated following the same methodology above described for thesynthesis of other (hydroxymethyl)pyrazoles (see example 6). Yield: 60%(170 mg, 0.4 mmol).

¹H NMR (300 MHz, CDCl₃, δ (ppm)): 6.18 (s, H-4 (pz), 2H), 4.38-4.34 (m,—CH₂, 4H), 3.99 (t, —CH₂, 4H), 3.49 (m, —CH₂, 2H), 3.34 (s, —OCH₃, 6H),3.30 (s, —OCH₃, 6H), 2.92 (t, —CH₂, 4H), 2.67 (t, —CH₂, 2H).

{3,5-(CH₃OCH₂)₂}pz(CH₂)₂N((CH₂)₂OMe)(CH₂)_(2{)3,5-(CH₂OCH₃)₂pz)}(compound 13): Compound 13 has been obtained by reacting a solution of2-(bis(2-(3,5-bis(methoxymethyl)-1H-pyrazol-1-yl)ethyl)amino)ethanol(170 mg, 0.4 mmol) in dry THF (10 mL) with NaH and CH₃I. Yield: 30% (46mg; 0.12 mmol).

¹H NMR (CDCl₃): δ_(H) 6.17 (s, H-4 (pz), 2H, 4.40-4.34 (m, —CH₂, 8H),4.07-3.95 (m, —CH₂, 4H), 3.35-3.23 (m, —OCH₃+—CH₂, 15+2H), 3.21-2.89 (m,—CH₂, 4H), 2.73-2.69 (m, —CH₂, 2H).

Example 7 Production of Tricarbonyl Rhenium Complexes with Chelators ofGeneral Formulae (I), (II) or (III)

Although the preferred complexes according to this invention, in thatthey are useful for diagnosis, are the ^(99m)Tc complexes, the Recomplexes are used as a model to characterise them, as the ^(99m)Tccomplexes are not available in sufficient quantities to be characterisedby the normal analytical techniques, such as NMR. After the Re complexeshave been thus characterised, HPLC is performed on both the Re complexesand the corresponding ^(99m)Tc complexes to determine if the retentiontime is the same for both.

The synthesis of the Re complexes was done by reaction of the chelatorsof general formula (I), (II) or (III) with common Re(I) startingmaterials, such as (NEt₄)₂[Re(CO)₃Br₃] or [Re(CO)₃(H₂O)₃]Br (FIG. 8). Inall the complexes the chelators act as neutral and tridentate, asconfirmed by ¹H and ¹³C NMR spectroscopy (FIGS. 9 and 10) and by X-raydiffraction analysis (FIG. 11).

Example 7a Tricarbonyl Rhenium Complex ofO-methyl-1,1,1-tris(pyrazolyl)ethanol (compound 1):[Re(CO)₃{CH₃OCH₂C(pz)₃}] (compound 14)

A solution of (NEt₄)₂[Re(CO)₃Br₃] (80 mg, 0.104 mmol) and compound 1 (27mg, 0.104 mmol) in ethanol (15 mL) was heated under reflux for about 16h. The solvent was removed under vacuum and the residue extracted withTHF. Compound 14 was recovered as a beige solid, after removal of THF,washing with toluene and drying under vacuum. Yield: 71% (45 mg, 0.074mmol).

Analysis calculated for C₁₅H₁₄N₆O₄BrRe: C, 29.61%; H, 2.32%; N, 13.81%.Found: C, 28.27%; H, 2.48%; N, 11.23%. IR Data (KBr, v/cm⁻¹): 1914 (vs)and 2042 (s) (C≡O).

¹H NMR (CDCl₃, δ_(H) ppm): 8.98 (1H, br, H-3/5 (pz)), 8.49 (2H, br,H-3/5 (pz)), 8.01 (3H, br, H-3/5 (pz)), 6.58 (3H, br, H-4 (pz)), 6.12(2H, s, CH ₂), 4.06 (3H, s, CH ₃). ¹³C NMR (CDCl₃, δ_(C) ppm): 193.8(br, CO), 147.2 (C-3/5 (pz)), 135.8 (C-3/5 (pz)), 134.6 (C-3/5 (pz)),109.9 (C-4 (pz)), 109.0 (C-4 (pz)), 85.2 (Cpz₃), 70.4 (CH₂), 60.7 (CH₃).

Example 7b Tricarbonyl Rhenium Complex of O—ethyl-1,1,1-tris(pyrazolyl)ethanol (compound 2):[Re(CO)₃{CH₃CH₂OCH₂C(pz)₃}] (compound 15)

Complex 15 was synthesized as above described for compound 14 byreaction of (NEt₄)₂[Re(CO)₃Br₃] with CH₃CH₂OCH₂C(pz)₃ (2). However,compound 15 was always obtained slightly contaminated with [NEt₄]Br, dueto their similar solubilities in the most common solvents.

IR Data (KBr, v/cm⁻¹): 1926 (s), 1946 (s) and 2042 (s) (C≡O).

¹H NMR (CDCl₃, δ ppm): 9.22 (1H, br, H-3/5 (pz)), 8.49 (2H, d, H-3/5(pz)), 8.02 (2H, br, H-3/5 (pz)), 7.98 (1H, br, H-3/5 (pz)), 6.58 (3H,tr, H-4 (pz)), 6.27 (2H, s, CH ₂), 4.38 (2H, q, CH ₂), 1.37 (3H, tr, CH₃).

Example 7c Tricarbonyl Rhenium Complex ofO-n-propyl-1,1,1-tris(pyrazolyl)ethanol (compound 3):[Re(CO)₃{CH₃CH₂CH₂OCH₂C(pz)₃}] (compound 16)

A solution of (NEt₄)₂[Re(CO)₃Br₃] (100 mg, 0.13 mmol) and compound 3 (40mg, 0.14 mmol) in ethanol (15 mL) was heated under reflux for about 16h. The solvent was evaporated under vacuum and the residue was washedwith THF and water. The insoluble solid was dried under vacuum andformulated as compound 16. Yield: 30% (25 mg, 0.039 mmol).

Analysis calculated for C₁₇H₁₈N₆O₄BrRe: C, 32.08%; H, 2.85%; N, 13.20%.Found: C, 31.39%; H, 2.41%; N, 12.72%. IR Data (KBr, v/cm⁻¹): 1940 (vs)and 2042 (s) (C≡O).

¹H NMR (CDCl₃, δ ppm): 9.20 (1H, br, H-3/5 (pz)), 8.39 (2H, br, H-3/5(pz)), 8.04 (2H, br, H-3/5 (pz)), 7.99 (1H, br, H-3/5 (pz)), 6.58 (3H,br, H-4 (pz)), 6.25 (2H, br, CH ₂), 4.27 (2H, br, CH ₂), 1.75 (2H, br,CH ₂), 0.98 (3H, br, CH ₃).

Example 7d Tricarbonyl Rhenium Complex oftris[3,5-(methoxymethyl)pyrazolyl]methane (compound 7)

[Re(CO)₃{HC[3,5-(CH₃OCH₂)₂pz]₃}] (compound 17)

Complex 17 was obtained by reacting (NEt₄)₂[Re(CO)₃(H₂O)₃]Br withHC[3,5-(CH₃OCH₂)₂pz]₃ (compound 7) in ethanol under reflux for about 16h. IR and ¹H NMR analyses of the crude product, after removal of thesolvent under vacuum, have shown the formation of the desired compound.

IR Data (KBr, v/cm⁻¹): 1945 (vs) and 2037 (s) (C≡O).

¹H NMR (CDCl₃, δ ppm): 9.47 (1H, s, CH), 6.70 (3H, s, H-4 (pz)), 4.96(6H, s, CH ₂), 4.63 (6H, s, CH ₂) 3.55 (9H, s, CH ₃) 3.50 (9H, s, CH ₃).

Example 8 Production of Tricarbonyl ^(99m)Tc Complexes with Chelators ofGeneral Formula (I) (FIG. 12)

In a nitrogen-purged glass vial, 100 μL of a 10⁻³10⁻² M aqueous solutionof compounds 1-3, 7, 10 and of the already described ligands HC(pz)₃ andHC(3,5-Me₂pz)₃ were added to 900 μL (5-15 mCi) of the organometallicprecursor fac-[^(99m)Tc(OH₂)₃(CO)₃]⁺, and the mixture was heated at70-100° C. for 30-60 min. After this time, complexes 14a-18a, 23a and24a have been obtained in >90% yield, as checked by gradient HPLCanalysis (100% aqueous 0.1% CF₃COOH solution→100% CH₃CN (or 100% CH₃OH))using a Nucleosil column (10 μm, 250 mm×4 mm) The chemical identity ofthe ^(99m)Tc complexes was confirmed by comparing their HPLCchromatograms with the HPLC profile of the analogue Re complexes (FIG.13). The characterization of the ^(99m)Tc complexes comprised also thedetermination of the octanol-water partition coefficient (log P_(o/w))values by the multiple back extraction method under physiologicalconditions (n-octanol/0.1 M PBS, pH 7.4). The retention time and logP_(o/w) values obtained for complexes 14a-18a, 23a and 24a are given inTable 1.

TABLE 1 HPLC retention time (t_(R)) and log P_(o/w) values for complexes6a-11a Complex t_(R)(min) log P_(o/w) 14a 20.6 0.32 15a 21.7 0.68 16a20.8 1.18 17a 20.1 0.58 18a 20.8 0.64 23a 19.6 1.2 24a 16.6 0.55

Example 9 Biodistribution of the ^(99m)Tc complexes with Chelators ofGeneral Formula (I)

These studies have been designed as a preliminary screening tool toevaluate the biological profile of the cationic tricarbonyl complexes.The biodistribution of the complexes was evaluated in groups of 5 femaleCD-1 mice (randomly bred, Charles River) weighing approximately 20-25 geach and have been performed according to EEC Legislation (National Law129/92) on ethical and animal care Animals were intravenously injectedwith 100 μl (1.5-8.0 MBq) of each preparation via the tail vein and weremaintained on normal diet ad libitum. Mice were killed by cervicaldislocation at 1 h and 2 h p.i. The injected radioactive dose and theradioactivity remaining in the animal after sacrifice were measured in adose calibrator (Aloka, Curiemeter IGC-3, Tokyo, Japan). The differencebetween the radioactivity in the injected and sacrificed animal wasassumed to be due to total excretion from whole body animal Bloodsamples were taken by cardiac puncture at sacrifice. Tissue samples ofthe main organs were then removed, weighted and counted in a gammacounter (Berthold). Biodistribution results were expressed as percentageof the injected dose per organ (% ID/organ) and/or per gram tissue (%ID/g). For blood, total activity was calculated assuming that this organconstitutes 6% of the total weight, respectively. The remaining activityin the carcass was also measured in a dose calibrator. Biodistributiondata for some ^(99m)Tc complexes are shown in Tables 2 and 3. Table 4also shows a direct comparison of biodistribution and relevant ratiosfor complexes 17a and 18a and the heart imaging agent ^(99m)Tc-Sestamibiin the same animal model (% ID/g of wet organ).

TABLE 2 Biodistribution data for complexes 14a-18a, 23a, 24a (% ID/g ofwet organ). (23a) (24a) (14a) (15a) Organ 1 h 2 h 1 h 2 h 1 h 2 h 1 h 2h Blood 1.4 ± 0.1 1.3 ± 0.2 5.4 ± 1.2 1.6 ± 0.3 1.5 ± 0.1 0.8 ± 0.1 0.5± 0.2 0.3 ± 0.1 Liver 18.7 ± 4.7  19.1 ± 5.3  9.9 ± 2.7 4.9 ± 1.3 6.9 ±2.3 6.2 ± 2.1 3.8 ± 2.0 1.6 ± 0.6 Heart 4.1 ± 0.7 4.3 ± 1.8 1.9 ± 0.31.4 ± 0.3 1.3 ± 0.3 0.9 ± 0.2 3.6 ± 0.5 1.8 ± 0.7 Lung 3.2 ± 0.3 2.1 ±0.7 1.4 ± 0.3 1.2 ± 0.2 0.8 ± 0.2 0.8 ± 0.3 0.9 ± 0.1 0.6 ± 0.3 Kidney44.7 ± 5.1  40.0 ± 5.2  7.2 ± 0.5 3.9 ± 0.8 3.3 ± 0.9 2.7 ± 0.4 5.0 ±1.4 2.8 ± 0.5 (16a) (17a) (18a) Organ 1 h 2 h 1 h 2 h 1 h 2 h Blood 0.36± 0.06 0.22 ± 0.06 0.9 ± 0.1 0.9 ± 0.2 0.52 ± 0.09 0.34 ± 0.02 Liver 4.3± 1.6 2.1 ± 0.5 8.7 ± 1.8 5.3 ± 0.9 5.1 ± 0.9 5.0 ± 2.4 Heart 1.8 ± 0.40.4 ± 0.2 10.1 ± 3.1  9.9 ± 3.1 18.2 ± 3.2  15.8 ± 2.1  Lung 0.9 ± 0.50.29 ± 0.04 3.1 ± 0.8 2.3 ± 0.8 4.3 ± 1.3 2.2 ± 0.3 Kidney 8.6 ± 2.1 7.8± 3.0 25.0 ± 3.3  14.7 ± 1.8  16.1 ± 2.3  9.9 ± 0.9

TABLE 3 Heart/Blood, Heart/Liver and Heart/Lung ratios for complexes14a-18a, 23a and 24a. (23a) (24a) (14a) (15a) Ratios 1 h 2 h 1 h 2 h 1 h2 h 1 h 2 h Heart/Blood 2.6 ± 0.3 3.8 ± 0.1 0.34 ± 0.06 0.9 ± 0.2 0.9 ±0.1 1.1 ± 0.1 8.2 ± 2.9 9.6 ± 0.6 Heart/Liver 0.22 ± 0.03 0.25 ± 0.070.20 ± 0.04 0.29 ± 0.05 0.18 ± 0.03 0.3 ± 0.1 1.4 ± 0.9 1.3 ± 0.7Heart/Lung 1.3 ± 0.1 2.0 ± 0.3 1.3 ± 0.3 1.2 ± 0.3 1.7 ± 0.3 1.6 ± 0.44.0 ± 0.7 4.3 ± 1.4 (16a) (17a) (18a) Ratios 1 h 2 h 1 h 2 h 1 h 2 hHeart/Blood 4.6 ± 0.9 1.6 ± 0.5 11.2 ± 3.5  11.5 ± 2.2  35.0 ± 5.3  47.3± 2.3  Heart/Liver 0.5 ± 0.2 0.15 ± 0.05 1.1 ± 0.2 1.6 ± 0.5 3.5 ± 0.93.5 ± 0.9 Heart/Lung 2.2 ± 0.8 3.3 ± 0.4 4.6 ± 1.8 4.9 ± 1.1 7.0 ± 0.6

TABLE 4 Biodistribution data and relevant ratios for complexes 17a and18a and the heart imaging agent ^(99m)Tc-Sestamibi (% ID/g of wetorgan). (17a) (18a) ^(99m)Tc-Sestamibi 5 min 60 min 120 min 5 min 60 min120 min 5 min 60 min 120 min Organ Blood 0.9 ± 0.1 0.9 ± 0.2 1.14 ± 0.090.52 ± 0.09 0.34 ± 0.02 2.0 ± 0.4 1.2 ± 0.4 1.1 ± 0.3 Liver 8.7 ± 1.85.3 ± 0.9 9.2 ± 0.9 5.1 ± 0.9 5.0 ± 2.4 9.0 ± 1.8 5.6 ± 0.3 5.0 ± 2.1Heart 10.1 ± 3.1  9.9 ± 3.1 15.8 ± 1.7  18.2 ± 3.2  15.8 ± 2.1  9.4 ±0.4 8.0 ± 0.6 7.9 ± 1.0 Lung 3.1 ± 0.8 2.3 ± 0.8 4.2 ± 0.5 4.3 ± 1.3 2.2± 0.3 2.4 ± 0.6 1.3 ± 0.2 0.9 ± 0.2 Kidney 25.0 ± 3.3  14.7 ± 1.8  43.4± 4.3  16.1 ± 2.3  9.9 ± 0.9 34.2 ± 2.4  14.8 ± 6.1  9.7 ± 1.8 RatiosHeart/Blood 11.2 ± 3.5  11.5 ± 2.2  13.9 ± 1.2  35.0 ± 5.3  47.3 ± 2.3 4.1 ± 0.7 7.9 ± 3.6 7.4 ± 2.3 Heart/Liver 1.1 ± 0.2 1.6 ± 0.5 1.7 ± 0.33.5 ± 0.9 3.5 ± 0.9 0.9 ± 0.2 1.4 ± 0.1 1.8 ± 0.7 Heart/Lung 3.3 ± 0.44.6 ± 1.8 3.8 ± 0.4 4.9 ± 1.1 7.0 ± 0.6 3.5 ± 0.8 6.3 ± 0.6 9.2 ± 1.1

What is claimed is:
 1. A compound comprising Formula (I), (II), or(III):

wherein, n is an integer selected from 1 or 2, and at least one of R1,R2, R3, and R4 is a linear group of the type —R^(x)—O—R^(Y) or amacrocyclic ether group, and each of the other three R groups isindependently hydrogen; a linear or branched, saturated or unsaturatedC₁ to C₉ alkyl; a saturated or unsaturated carbocyclic group; asaturated or unsaturated heterocyclic or heteroaliphatic group with oneor more atoms selected from O, N and S, wherein said carbocyclics,heterocyclics and heteroaliphatics are optionally substituted by one ormore linear or branched, saturated or unsaturated C₁ to C₉ alkyls; anether group —R^(x)—O—R^(Y) or [(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8,z=2-5), wherein R^(x) and R^(Y) are independently linear or branched,saturated or unsaturated C₁ to C₉ alkyl, or saturated or unsaturatedcarbocyclics, any of which alkyl and/or carbocyclic groups may besubstituted or unsubstituted, and provided that when the tridentatechelator is of the type of formula (I), when R1 is —R^(x)—O—R^(Y)wherein R^(Y) is substituted, and R2, R3, and R4 are each hydrogen,R^(Y) is not substituted apically by a further tris(pyrazolyl)methanemoiety; and when R1 is —R^(x)—O—R^(Y) and R2, R3, and R4 are eachhydrogen, R1 cannot be —CH₂—O—CH₂—(p-^(t)Bu-C₆H₄).
 2. The compound ofclaim 1, wherein the compound is complexed with a ^(99m)Tc radioisotope.3. A compound comprising Formula (I):

wherein, at least one of R1, R2, R3, and R4 is a linear or macrocyclicether group of the type —R^(x)—O—R^(Y) or [(CH₂)_(x)O]_(y) (CH₂)_(z)(x=2-3, y=3-8, z=2-5), respectively, and each of the other three Rgroups is independently hydrogen; a linear or branched, saturated orunsaturated C₁ to C₉ alkyl; a saturated or unsaturated carbocyclicgroup; a saturated or unsaturated heterocyclic or heteroaliphatic groupwith one or more atoms selected from O, N and S, wherein saidcarbocyclics, heterocyclics and heteroaliphatics are optionallysubstituted by one or more linear or branched, saturated or unsaturatedC₁ to C₉ alkyls; an ether group —R^(x)—O—R^(Y) or[(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5), wherein R^(x) and R^(Y)are independently linear or branched, saturated or unsaturated C₁ to C₉alkyl, or saturated or unsaturated carbocyclics, any of which alkyland/or carbocyclic groups may be substituted or unsubstituted, providedthat when R1 is —R^(x)—O—R^(Y) wherein R^(Y) is substituted, and R2, R3,and R4 are each H, R^(Y) is not substituted apically by a furthertris(pyrazolyl)methane moiety; and when R1 is —R^(x)—O—R^(Y) and R2, R3,and R4 are each H, R1 cannot be —CH₂—O—CH₂—(p-^(t)Bu-C₆H₄).
 4. Thecomposition of claim 3, wherein R1 is chosen from CH₂OCH₃, CH₂OCH₂CH₃,and CH₂OCH₂CH₂CH₃.
 5. The composition of claim 3, wherein R2, R3, and R4are hydrogen.
 6. The composition of claim 3, wherein R1 is hydrogen; R2and R4 are C₁ to C₃ alkyl; and R3 is the ether group —R^(x)—O—R^(Y),where R^(x) and R^(Y) are linear C₁ to C₉ alkyl.
 7. The composition ofclaim 6, wherein R2 and R4 are methyl, and R3 is CH₂CH₂OCH₃.
 8. Thecomposition of claim 3, wherein R1 and R3 are hydrogen, and R2 and R4are the ether group —R^(x)—O—R^(Y), where R^(x) and R^(Y) are linear C₁to C₉ alkyl.
 9. The composition of claim 8, wherein R2 and R4 areCH₂OCH₃.
 10. The composition of claim 3, wherein R1 is hydrogen and R2,R3, and R4 are the ether group —R^(x)—O—R^(Y), where R^(x) and R^(Y) arelinear C₁ to C₉ alkyl.
 11. The composition of claim 10, wherein R2, R3,and R4 are CH₂OCH₃.
 12. The composition of claim 3, wherein R1, R2, andR4 are hydrogen and R3 is the ether group —R^(x)—O—R^(Y), where R^(x)and R^(Y) are linear C₁ to C₉ alkyl.
 13. The composition of claim 12,wherein R3 is CH₂OCH₃.
 14. The composition of claim 12, wherein R3 isCH₂OCH₂CH₃.
 15. The composition of claim 3, wherein R2, R3, and R4 arehydrogen.
 16. A compound comprising Formula (II):

wherein, n is an integer selected from 1 or 2, and at least one of R1,R2, R3, and R4 is a linear or macrocyclic ether group of the type—R^(x)—O—R^(Y) or [(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5),respectively, and each of the other three R groups is independentlyhydrogen; a linear or branched, saturated or unsaturated C₁ to C₉ alkyl;a saturated or unsaturated carbocyclic group; a saturated or unsaturatedheterocyclic or heteroaliphatic group with one or more atoms selectedfrom O, N and S, wherein said carbocyclics, heterocyclics andheteroaliphatics are optionally substituted by one or more linear orbranched, saturated or unsaturated C₁ to C₉ alkyls; an ether group—R^(x)—O—R^(Y) or [(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5),wherein R^(x) and R^(Y) are independently linear or branched, saturatedor unsaturated C₁ to C₉ alkyl, or saturated or unsaturated carbocyclics,any of which alkyl and/or carbocyclic groups may be substituted orunsubstituted.
 17. The composition of claim 16, wherein n is equal to 1;R1 is the ether group —R^(x)—O—R^(Y), where R^(x) and R^(Y) are linearC₁ to C₉ alkyl; and R2, R3, and R4 are hydrogen.
 18. The composition ofclaim 17, wherein R1 is CH₂CH₂OCH₃.
 19. A compound comprising Formula(III):

wherein, n is an integer selected from 1 or 2, and at least one of R1,R2, R3, and R4 is a linear or macrocyclic ether group of the type—R^(x)—O—R^(Y) or [(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5),respectively, and each of the other three R groups is independentlyhydrogen; a linear or branched, saturated or unsaturated C₁ to C₉ alkyl;a saturated or unsaturated carbocyclic group; a saturated or unsaturatedheterocyclic or heteroaliphatic group with one or more atoms selectedfrom O, N and S, wherein said carbocyclics, heterocyclics andheteroaliphatics are optionally substituted by one or more linear orbranched, saturated or unsaturated C₁ to C₉ alkyls; an ether group—R^(x)—O—R^(Y) or [(CH₂)_(x)O]_(y)(CH₂)_(z) (x=2-3, y=3-8, z=2-5),wherein R^(x) and R^(Y) are independently linear or branched, saturatedor unsaturated C₁ to C₉ alkyl, or saturated or unsaturated carbocyclics,any of which alkyl and/or carbocyclic groups may be substituted orunsubstituted.
 20. The composition of claim 19, wherein n is equal to 2;R1, R2, and R4 are the ether group —R^(x)—O—R^(Y), where R^(x) and R^(Y)are linear C₁ to C₉ alkyl; and R3 is hydrogen.
 21. The composition ofclaim 20, wherein R1 is CH₂CH₂OCH₃, and R2 and R4 are CH₂OCH₃.